Summary The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of ‘orphan’ T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A*02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens, which enables the facile identification of tumor antigens through unbiased screening.
Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastrictissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastriccancer surgery.mass spectrometry imaging | biostatistics | surgical margins | intraoperative diagnosis G astric cancer is currently the second most common cause of cancer death worldwide after lung cancer (1). Surgical resection of gastrointestinal (GI) cancers remains the main treatment option for these diseases. It is well accepted that complete resection of the tumor is associated with an improved prognosis for most types of solid malignancies. Positive margins, defined as the presence of tumor cells at the resected specimen edge and/or in the resection bed, have been associated with increased local recurrence and decreased overall survival in many cancers (2). Margin-negative surgical resection has the greatest potential to offer prolonged disease-free and overall-survival benefit across the entire spectrum of GI cancers (2-5). The evaluation is commonly performed in a room close to the operating room, where the proximal and distal margins of the surgical specimen are frozen, sectioned, stained, and read by pathologists before completion of the operation. The results of the intraoperative pathologic evaluation of the margins are communicated to the surgeon and consequently guide the surgeon's subsequent actions. For example, in the case of positive margins, surgical resection is extended by removing additional tissue around the tumor, which commonly demands a second round of margin evaluation by pathology. However, because of freezing artifacts on tissue morphology, intraoperative fro...
Much has been said and written about the importance of teams to the success of organisations and emphasis has been given to the benefits of team‐building activities to achieving both team and organisational effectiveness. Describes attempts to move beyond team building and to link organisational development to team effectiveness in a coherent way. In order to achieve this goal, a team effectiveness audit tool has been devised which is based on individual self‐assessment. The audit tool focuses on six domains considered to be important in effective teams. The self‐report audit tool has now been used by over 140 teams across a range of public‐sector organisations and this has enabled a significant database to be built up. This provides a large normative data set against which individual team performance can be gauged. Focuses on data derived from 37 teams within an integrated acute and community health and social services (HSS) trust. Overall the team effectiveness audit tool has been well received and has proven to be an effective mechanism of linking individual and team performance with organisational‐management objectives.
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